Endogenously synthesized antigenic determinants are generally presented on major histocompatibility complex (MHC) class I molecules, whereas exogenous determinants are presented by MHC class II molecules. Here, it is shown that exogenous antigens chaperoned by a heat shock protein can be channeled into the endogenous pathway, presented by MHC class I molecules, and recognized by CD8⁺ T lymphocytes. This pathway is functional only in a subset of macrophages among the cell types tested. These observations provide a basis for the tumor-specific and virus-specific immunogenicity of cognate heat shock protein preparations and offer a mechanism for the classical phenomenon of cross-priming.